Introduction
Dietary restriction (DR) has been linked to longevity and improved metabolism in various animal models. Reducing dietary intake affects cellular signaling pathways, impacting nutrient sensors like mTORC1, Sirt1, and AMPK, which regulate aging and metabolic pathways. Recent studies suggest that the ratio of dietary protein to carbohydrates is a critical determinant of the effect of a controlled diet on longevity and metabolic health. Branched-chain amino acids (BCAAs) are associated with aging-related pathways and metabolic health. BCAAs constitute approximately 25% of the amino acids in individual proteins in humans and are considered essential amino acids. Restriction of BCAA intake increases longevity and health span in rodents, suggesting that BCAAs or their metabolic pathways could be critical in stimulating the aging process and decreasing metabolic health in mammals. This article explores the role of BCAAs and their metabolism in regulating human disease and age-associated metabolic pathways, focusing on metabolic tissues, and discusses the potential benefits and considerations of BCAA supplementation on a ketogenic diet.
Understanding BCAAs
BCAAs consist of three essential amino acids: leucine, isoleucine, and valine. These amino acids are crucial because the body cannot produce them on its own, requiring them to be obtained through diet. After consuming a protein diet, digested BCAAs in the intestinal lumen are taken up by Na+-dependent transporters of the apical membrane of intestinal epithelial cells. They are then released to the bloodstream by facilitated transport and are specifically transported across cell membranes of tissues mainly by the L-type Na+-dependent cotransporter LAT1 and its heterodimeric partner 4F2hc.
Metabolic Pathways of BCAAs
The first two steps of BCAA degradation are carried out by branched amino acid aminotransferase (BCAT) and branched-chain keto acid dehydrogenase (BCKDH). BCAT consists of two different isozymes, BCAT1 and BCAT2. BCAT1 is a cytosolic enzyme found only in limited tissues, such as embryonic tissues, the brain, and the ovary. However, the mitochondrial enzyme BCAT2 is ubiquitously expressed in various tissues, including skeletal muscle and adipose tissue. BCAT acts upon all three BCAAs and converts them into branched-chain keto acids (BCKAs) and glutamate. In the next step, BCKAs are converted into distinct forms of branched-chain acyl-CoA by the BCKDH complex. The BCKDH complex is an α-keto acid dehydrogenase complex that includes a pyruvate dehydrogenase complex and an α-ketoglutarate dehydrogenase complex.
Branched-chain acyl-CoA is degraded in parallel. Isobutyryl CoA, generated from the catabolic pathway of valine, is eventually converted to propionyl CoA and enters the tricarboxylic acid (TCA) cycle via a form of succinyl CoA. During the degradation of isoleucine, the intermediate 2-methylbutyryl CoA is converted to acetyl-CoA and propionyl CoA, each of which can eventually join the TCA cycle. Finally, isovaleryl CoA, an intermediate of leucine catabolism, is converted to β-hydroxy-β-methylglutaryl CoA (HMG CoA), which is eventually converted to acetyl-CoA. The degradative pathway for these branched-chain acyl-CoA molecules also involves the generation of NADH and FAD(2H). BCAA catabolism functions as a key pathway for energy generation by mitochondrial oxidative phosphorylation, or BCAA catabolites could funnel into the generation of fatty acids, cholesterol, ketone bodies, or glucose depending on the nutritional status or the specific needs of the cells and organisms.
Regulation of BCAA Catabolism
The regulation of BCAA catabolism occurs mainly in its rate-limiting step, the conversion of BCKA into branched-chain acyl-CoA by the BCKDH complex, which is located in the inner mitochondrial membrane and is allosterically inhibited by its major products, branched-chain acyl-CoA and NADH. The phosphorylation status of this complex dictates its activity. BCKDH kinase (BCKDK) catalyzes the phosphorylation of serine 293 of BCKDHA, inhibiting the activity of the BCKDH complex. Conversely, protein phosphatase 2Cm (PP2Cm) functions as a specific phosphatase that removes a phosphate from serine 293 of BCKDHA, thus activating the BCKDH complex.
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Chronic regulation of BCAA catabolism is achieved via the transcriptional regulation of gene expression. Krȕppel-like factor 15 (KLF15) is involved in the transcriptional activation of various genes involved in BCAA catabolism in cardiac muscle. Peroxisome proliferator-activated receptor (PPAR) γ regulates BCAA metabolism, at least in adipose tissue. Treatment with TZD increased the expression of genes involved in BCAA catabolism, such as BCAT2, BCKDHA, BCKDHB, DBT and DLD, in human adipose tissue.
Role of BCAA Catabolism in Cellular Physiology
Skeletal Muscle and Liver
Skeletal muscle is a major site for BCAA catabolism. Exercise increases BCAA catabolism in skeletal muscle. BCKAs originating from skeletal muscle can be utilized in the liver in catabolic pathways to produce ATP via mitochondrial oxidative phosphorylation and the production of lipids such as fatty acids and cholesterol. In addition, α-ketoisocaproic acid (BCKA from leucine) and α-ketomethylvaleric acid (BCKA from isoleucine) can be utilized to generate glucose (via gluconeogenesis) and ketone bodies depending on metabolic needs during BCKA catabolism.
Adipose Tissues
Adipose tissue plays a critical role in BCAA catabolism. BCAA utilization or catabolism in adipose tissue is critical for maintaining BCAA homeostasis at the systemic level. Brown adipose tissue (BAT) utilizes BCAA to control adaptive thermogenesis in response to cold exposure. BCAA catabolism in BAT is essential for the metabolic health of the organism by controlling thermogenic capacity, whole-body BCAA homeostasis, and systemic energy expenditure.
Brain
BCAAs can readily cross the blood‒brain barrier (BBB). In the brain, BCAAs are involved in key cellular functions, such as glutamate metabolism, protein synthesis, and energy generation. BCAA metabolism in the brain is essential for maintaining neuronal glutamate levels. BCAAs are also essential for the generation of Gamma-aminobutyric acid (GABA).
Systemic Control of BCAA Catabolism
BCAA catabolism linked to the TCA cycle is found in most tissues, including skeletal muscle, BAT, kidney, liver, heart, and pancreas. In healthy rodents, insulin or pharmacological activation of BCKDH increases BCAA catabolism in skeletal muscle. In an insulin-resistant state, BCAA catabolism is almost completely blocked in adipose tissue and the liver and is shifted to cardiac and skeletal muscle.
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Diseases Associated with BCAA Catabolism
Maple Syrup Urine Disease (MSUD)
Maple syrup urine disease (MSUD) is an autosomal recessive genetic disorder that originates from mutations in genes for the BCKDH complex, such as BCKDHA/B, DBT, and DLD. As a result of the production of the defunct BCKDH enzyme complex, the plasma levels of BCAA and its immediate catabolite BCKA are elevated.
BCAAs and Ketogenic Diet
The ketogenic diet is characterized by high fat intake, moderate protein, and very low carbohydrate consumption, shifting the body's primary fuel source from glucose to ketones.
Do BCAAs Break Ketosis?
BCAAs themselves do not contain glucose and do not directly trigger a rise in blood sugar. Leucine and isoleucine are ketogenic, converting into ketones, while valine is glucogenic, converting into glucose. However, at a dose of about 3-5 grams, valine is unlikely to disrupt ketosis.
Benefits of BCAAs on Keto
- Muscle Preservation: Ketosis doesn't automatically protect muscle tissue. BCAAs can help maintain lean muscle mass, especially when training hard or in a calorie deficit.
- Alternative to Whey Protein: BCAAs offer a way to support muscle without significantly increasing protein macros, which can be crucial on a keto diet where excess protein can convert into glucose.
- Recovery: BCAAs can aid in reducing delayed onset muscle soreness (DOMS), helping you recover faster after workouts.
What to Avoid in BCAA Supplements
- Flavorings that can have hidden carbs
- Artificial sweeteners like sucralose or acesulfame-K
- Citric acid or maltodextrins (they can spike insulin)
- BCAAs in a low leucine ratio
BCAA Supplementation: Benefits and Considerations
BCAA supplements have been a bodybuilding staple since the 1980s due to their effectiveness in building muscle and speeding up recovery.
Proven Benefits of BCAAs
- Increased Muscle Growth: Leucine activates muscle protein synthesis.
- Decreased Muscle Soreness: BCAAs can decrease muscle damage, reducing the length and severity of DOMS.
- Reduced Exercise-Induced Fatigue: BCAAs can alter levels of certain chemicals in the brain, such as serotonin, potentially decreasing exercise-induced fatigue.
- Prevention of Muscle Wasting: BCAA supplements can prevent the breakdown of protein in certain populations with muscle wasting.
- Support Liver Health: BCAA supplements may improve the health outcomes of people with liver disease and potentially protect against liver cancer.
Food Sources of BCAAs
BCAAs are available in various protein-rich foods, including meat, eggs, and dairy products. Consuming enough protein in your diet may make BCAA supplements unnecessary.
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BCAAs in Hyperammonemic Conditions
In hyperammonemic states, such as liver cirrhosis, urea cycle disorders, and strenuous exercise, BCAA catabolism is activated, leading to decreased BCAA concentrations. BCAAs are recommended to improve mental functions, protein balance, and muscle performance in these conditions.
BCKAs as Alternatives to BCAAs
Branched-chain keto acids (BCKAs) may offer advantages over BCAAs in hyperammonemic conditions. BCKA administration may decrease ammonia production, attenuate cataplerosis, correct amino acid imbalance, and improve protein balance.
Amino-Boosted Keto Diet
Dr. Fred Pescatore suggests a turbocharged keto diet by increasing amino acid intake, which stimulates the body to replace fat with lean muscle. He recommends skipping amino-deficient processed meats and aiming for a variety of high-quality protein sources. Branched-chain amino acids (BCAAs) naturally stimulate the production of fat-burning hormones.
Practical Tips for Incorporating BCAAs into a Keto Diet
- Choose Pure BCAA Supplements: Opt for unflavored BCAA supplements to avoid hidden carbs and artificial sweeteners.
- Time Your Intake: Consider taking BCAAs before, during, or after workouts to support muscle recovery and reduce fatigue.
- Prioritize Protein Variety: Include a variety of protein sources in your diet to ensure you're getting a full spectrum of amino acids.
- Monitor Your Ketone Levels: Track your ketone levels to ensure that BCAA supplementation is not negatively impacting your ketosis.
- Consult a Professional: Work with a healthcare provider or registered dietitian to determine the right BCAA dosage and timing for your individual needs.